The invention relates to a process for preparing 4,6-diaminopyrimido[5,4-d]pyrimidines of formula I, 
wherein R1, R2, R3, and R4 are defined as specified, from a compound of formula II, 
wherein R1, R2, R3, and R4 are defined as specified and PG1 denotes a suitable protecting group.
4,6-diaminopyrimido[5,4-d]pyrimidines are known for example from WO 97/32880 and are valuable pharmaceutical compositions which have, in particular, an inhibitory effect on signal transduction mediated by tyrosine kinases.
However, the method of preparation described therein is unsuitable for production on an industrial scale as the desired products are described as being obtained from starting materials which are not easily accessible, such as 4-anilino-6-methylsulphinyl-pyrimido[5,4-d]pyrimidines or 4-anilino-6-methylsulphonylpyrimido[5,4-d]pyrimidines which, when reacted, give off foul-smelling and toxic thiols which lead to contamination of the products.
The aim of the present invention is therefore to provide a process which makes it possible to synthesise, work up, purify and isolate 4,6-diaminopyrimido[5,4-d]pyrimidines of formula I on an industrial scale while overcoming the disadvantages mentioned above.
Surprisingly, it has been found that 4,6-diaminopyrimido[5,4-d]pyrimidines of formula I
wherein
R1 denotes a hydrogen atom or a C1-C6 alkyl group,
R2 denotes an optionally substituted C6-C10 aryl group,
R3 denotes a hydrogen atom or a C1-C6 alkyl group, and
R4 denotes a hydrogen atom or an optionally substituted C1-C6 alkyl, C3-C6 alkenyl, C3-C8 cycloalkyl or a 4- to 7-membered, nitrogen-containing heterocyclyl group, or
R3 and R4 together with the nitrogen atom linked to them denote an optionally substituted heterocyclyl group,
can be prepared in high yields and in a comparatively small number of steps, if the compound of formula II wherein R1, R2, R3, and R4 are as herein defined and
PG1 denotes a suitable protecting group,
(a) after the protecting group has been cleaved,
(b) is treated with a reducing agent, and
(c) is treated with an oxidising agent.
The invention thus relates to a process for preparing the compounds of formula I.
The invention further relates to a process for preparing a compound of formula II, by reacting a compound of formula III, 
wherein R1, R2 and PG1 are as herein defined,
with an amine of formula IV,
R3R4NHxe2x80x83xe2x80x83(IV) 
wherein R3 and R4 are as herein defined,
optionally in the presence of a base.
The invention further relates to a process for preparing a compound of formula III, wherein a compound of formula V, 
wherein R1 and R2 are as herein defined, is provided with a suitable protecting group (PG1).
The invention also relates to a process for preparing the compounds of formula V by reducing a compound of formula VI, 
wherein R1 and R2 are as herein defined; and a process for preparing a compound of formula VI by reacting 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine with an amine of formula VIII,
R1R2NHxe2x80x83xe2x80x83(VIII) 
wherein R1 and R2 are as herein defined.
The invention further relates to the new intermediate products of formulae II, III, V and VI.
The term xe2x80x9calkylxe2x80x9d as used hereinbefore and hereinafter with respect to the groups R1, R3 and/or R4 denotes a straight-chain or branched alkyl group having up to 6 C-atoms, preferably 1 to 4 C-atoms. Methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl are particularly preferred.
The term xe2x80x9calkenylxe2x80x9d as used hereinbefore and hereinafter with respect to the group R4 denotes a straight-chain or branched alkenyl group having up to 6 C-atoms, preferably 3 to 5 C-atoms. Allyl, but-2-enyl, but-3-enyl, pent-2-enyl, pent-3-enyl and pent-4-enyl are particularly preferred.
The term xe2x80x9carylxe2x80x9d as used hereinbefore and hereinafter with respect to the group R2 denotes an aromatic hydrocarbon group with 6 to 10 C-atoms, and aryl preferably denotes phenyl or naphthyl.
The term xe2x80x9csuitable protecting groupxe2x80x9d as used hereinbefore and hereinafter with respect to the group PG1 denotes a group familiar to those skilled in the art, e.g. a protecting group for amino groups as described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J. F. W. McOmie (Plenum Press), which is easily introduced, is inert to the subsequent reactions and can easily be cleaved again. Preferred protecting groups are the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, mesyl, tosyl or 2,4-dimethoxybenzyl group.
A protecting group used is cleaved hydrolytically, for example in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 50xc2x0 C.
A benzyl, methoxybenzyl or benzyloxycarbonyl is preferably cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50xc2x0 C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably from 3 to 5 bar.
A methoxybenzyl group can also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50xc2x0 C., but preferably at ambient temperature. However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol. A tert-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
The term xe2x80x9cheterocyclyl groupxe2x80x9d as used hereinbefore and hereinafter with respect to the group R3 or the group formed by R3 and R4 with the enclosed nitrogen atom denotes a saturated or unsaturated 4- to 7-membered, nitrogen-containing heterocyclyl group which may optionally contain, in addition to carbon atoms and at least one nitrogen atom, other heteroatoms selected from among oxygen and sulphur. The following heterocyclyl groups are preferred:
saturated 5- or 6-membered heterocyclyl groups which
contain one or two nitrogen atoms, particularly pyrrolidine, piperidyl and piperazyl, or
contain one nitrogen atom and an oxygen or sulphur atom, particularly morpholino and thiomorpholino.
If one of the groups R1 to R4 is referred to as an xe2x80x9coptionally substitutedxe2x80x9d group, this group may have one or more substituents, preferably 1, 2 or 3, particularly 1 or 2 substituents. These substituents are groups which are inert under the reaction conditions of the process according to the invention and do not provoke any noticeable side reactions. Preferred substituents are selected from among fluorine, chlorine, bromine, carboxy, carboxy-C1-3-alkyl, carboxy-C1-3-alkoxy, alkoxycarbonyl-C1-3-alkoxy, cyano, trifluoromethoxy, trifluoromethyl, C1-3-alkyl, hydroxy, C1-3-alkoxy, thiol, C1-3-alkylthio, phenyl-C1-3-alkoxy, amino, amino-C1-3-alkyl, C1-3-alkylamino C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino and di-(C1-3-alkyl)-amino-C1-3-alkyl.
In a preferred embodiment the groups R1 to R4 have the following meanings:
R1 denotes hydrogen or methyl, particularly hydrogen,
R2 denotes phenyl which may be substituted by one or two halogen atoms, particularly fluorine and/or chlorine, particularly 3-chloro-4-fluorophenyl,
R3 denotes hydrogen or methyl, particularly hydrogen, and
R4 denotes a 5- or 6-membered, nitrogen-containing heterocycle which may be substituted by one or two C1-3-alkyl groups, particularly 1-methylpiperid-4-yl, or
R3 and R4 together with the enclosed nitrogen atom form a 5- or 6-membered, nitrogen-containing heterocycle which may be substituted by one or two groups selected from among amino, C1-3-alkyl and di-(C1-3-alkyl)-amino-C1-3-alkyl, particularly amino, methyl and diethylaminomethyl, most preferably 4-amino-4-methylpiperid-1-yl.
In a preferred embodiment of the process according to the invention for preparing the compound of formula I:
in step (b) the compound obtained after the protecting group has been cleaved is hydrogenated in the presence of a transition metal catalyst or with hydrogen iodide optionally in the presence of phosphorus;
in step (c) the compound obtained in step (b) is treated with a peroxodisulphate or hydrogen peroxide.
Stage IIxe2x86x92I
Step (a)
The reaction of the compound of formula II, wherein PG1 is a C1-6 alkylcarbonyl group, with an aqueous base, preferably an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, is generally carried out at a temperature of 0xc2x0 C. to 150xc2x0 C., preferably 10xc2x0 C. to 100xc2x0 C., particularly at about 40 to 80xc2x0 C., optionally in the presence of an inert solvent, such as for example toluene or tetrahydrofuran and a protic solvent such as for example an alcohol or water or mixtures thereof. Preferably, 0.8 to 2, particularly 0.9 to 1.2 equivalents of the base are used to 1 equivalent of the compound of formula II.
In a particularly preferred embodiment about 0.9 to 1.1 equivalents of the sodium hydroxide in the form of an approximately 2 N aqueous solution are added at ambient temperature to a mixture of one equivalent of the compound of formula II and 5 to 20 parts methanol and 0.5 to 2 parts tetrahydrofuran (THF) based on 1 part compound of formula II and the mixture is heated to boiling for about 30 minutes to 2 hours. The mixture obtained is cooled and then further processed in the next step (b) without any other purification.
Step (b)
Dechlorination, Variant A:
The compound obtained after the protecting group has been cleaved is generally hydrogenated in the presence of a transition metal catalyst. The hydrogenation is generally carried out at a temperature of 20xc2x0 C. to 150xc2x0 C., preferably 40xc2x0 C. to 120xc2x0 C., particularly at the boiling temperature of the diluent, at a hydrogen pressure of about 1-120 bar, in the presence of an ether, such as for example diethylether, tert-butyl-methylether, dioxane or tetrahydrofuran, an alcohol, such as for example methanol, ethanol or isopropanol, a hydrocarbon, such as for example cyclohexane or n-hexane or mixtures thereof, particularly in the presence of the diluent obtained from step (a). Instead of the hydrogen formic acid may also be used as the hydrogen donor. In this case the reaction is generally carried out at normal pressure and 5 to 20 parts formic acid are used to 1 part of the catalyst. Preferably, 0.01 to 0.90, particularly 0.01 to 0.10 parts of a catalyst consisting of palladium and activated charcoal is used, containing 1 to 25%, preferably 5 to 15% palladium, to 1 part of the compound obtained after the protecting group has been cleaved. The hydrogenation is generally complete under the conditions described after 1 to 100 hours, preferably 10 to 80 hours. The crude product obtained is further processed in the next step after distillation of the solvent but no other purification.
In a particularly preferred embodiment the mixture obtained in step (a) is evaporated to dryness and the residue is taken up in THF and methanol. Pd/C (5-15%) is added and the mixture is refluxed. After the addition of 2 to 20 ml of formic acid, the mixture is stirred for 20 to 75 hours. It is left to cool to ambient temperature, filtered and evaporated to dryness. The residue is suspended in water and ethyl acetate, made weakly basic with a concentrated ammonia solution and stirred. The crystalline product is isolated, optionally recrystallised and dried.
Dechlorination, Variant B:
Alternatively, the compound obtained after the protecting group has been cleaved may be treated with hydrogen iodide, optionally in the presence of phosphorus. The reaction is generally carried out at a temperature of 20xc2x0 C. to 150xc2x0 C., preferably 40xc2x0 C. to 120xc2x0 C., particularly at the boiling temperature of the diluent, in the presence of a polar solvent, particularly a carboxylic acid, such as for example acetic acid or propionic acid, or an aqueous inorganic acid such as for example hydrochloric acid, hydrobromic acid, hydriodic acid or mixtures thereof or water. The reaction is generally carried out at normal pressure, preferably using 6 to 6.5 equivalents of hydrogen iodide in the form of a 30- to 60% aqueous solution based on 1 equivalent of the compound obtained after the protecting group has been cleaved. Preferably, the reaction is carried out in the presence of red phosphorus, using 1.0 to 3.0, preferably 1.8 to 2.5 equivalents phosphorus based on 1 equivalent of the compound obtained after the protecting group has been cleaved. The reaction is generally complete under the conditions specified after 0.5 to 10 hours, preferably 1 to 8 hours. The crude product obtained is further processed in the next step after distillation of the solvent but no other purification.
In a particularly preferred embodiment the mixture obtained in step (a) is evaporated down, taken up in glacial acetic acid and added dropwise to a suspension of red phosphorus in hydriodic acid (57%). The mixture is refluxed for 3 to 5 hours, decolorised and neutralised. The product is isolated and dried.
Step (c)
The compound obtained in step (b) is preferably oxidised in the presence of an aqueous acid with a peroxodisulphate or hydrogen peroxide. The oxidation is generally carried out at a temperature of 0xc2x0 C. to 150xc2x0 C., preferably 40xc2x0 C. to 120xc2x0 C., particularly at the boiling temperature of the diluent, in the presence of an acid, such as for example acetic acid, trifluoroacetic acid, hydrochloric acid, nitric acid, phosphoric acid or sulphuric acid or mixtures thereof, particularly in the presence of water. Preferably, 0.8 to 2.0, particularly 0.9 to 1.5 equivalents of the oxidising agent are used, particularly in the form of a 20 to 40% aqueous solution of hydrogen peroxide or a 20- to 50% aqueous solution of sodium peroxodisulphate based on one equivalent of the compound obtained in step (b). The oxidation is generally complete under the conditions specified after 10 minutes to 30 hours, preferably 15 minutes to 24 hours. The crude product obtained is further processed in the next step after distillation of the solvent but no other purification.
In a particularly preferred embodiment 1 equivalent of the compound obtained in step (b) is taken up in 5 to 15% sulphuric acid and at boiling temperature combined with 0.01 to 0.10 equivalents of potassium iodide and 1.0 to 2.0, preferably 1.2 to 1.5 equivalents of hydrogen peroxide in the form of a 35% solution. The mixture is stirred for 10 to 30 minutes and an aqueous solution of sodium bisulphite and ethanol is added. Then the mixture is allowed to cool slowly to ambient temperature and stirred. The product that crystallises out is filtered and dried.
In another particularly preferred embodiment 1 equivalent of the compound obtained in step (b) is taken up in a mixture of glacial acetic acid and water (20- to 40%) and combined with 1.0 to 2.0, preferably 1.1 to 1.6 equivalents of sodium peroxodisulphate in the form of an approximately 30 to 35% aqueous solution. The mixture is stirred for 30 to 300 minutes at a temperature of 20 to 75xc2x0 C. The solid formed is filtered off, suspended in water, neutralised with concentrated ammonia solution and extracted with ethyl acetate. The organic phase is separated off, dried and evaporated down. The residue is taken up in ethanol and converted into the hydrochloride of the compound of formula I by the addition of ethanolic HCl. The crystallised product is filtered off and dried.
Stage IIIxe2x86x92II
In a preferred embodiment of the process according to the invention for preparing the compound of formula II:
the reaction is carried out in the presence of a tertiary amine;
the reaction is carried out in a temperature range of 0xc2x0 C. to 150xc2x0 C.
The reaction with the amine of formula IV is expediently carried out in a diluent such as methanol, ethanol, isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulphoxide, ethyleneglycolmonomethylether, ethylenglycoldiethylether or sulpholane or mixtures of these diluents, optionally in the presence of an inorganic base, e.g. sodium carbonate or potassium hydroxide, or a tertiary organic base, e.g. triethylamine, N-ethyl-diisopropylamine or pyridine, while the latter may simultaneously serve as solvent, and optionally in the presence of a reaction accelerator such as a copper salt, a corresponding amino-hydrohalide or alkali metal halide at temperatures between 0 and 150xc2x0 C., but preferably at temperatures between 20 and 120xc2x0 C. The reaction may however also be carried out without a solvent or in an excess of the compound of general formula IV used. The reaction is generally carried out at normal pressure, using 0.8 to 2.0, preferably 0.9 to 1.5, particularly 1.0 to 1.5 equivalents of a compound of formula IV based on 1 equivalent of the compound of formula III. The reaction is generally complete under the conditions specified after 15 to 600 minutes, preferably 30 to 180 minutes. The crude product obtained is generally purified by recrystallisation or may be further processed in the next step without any other purification.
In a particularly preferred embodiment 0.8 to 1.8, preferably 1.0 to 1.6 equivalents of the amine of formula IV, particularly 1-methyl-4-aminopiperidine or 4-methylpiperidin-4-ylamine, is added dropwise to a mixture of 1 equivalent of the compound of formula III, THF and/or methanol and optionally 1 to 2 equivalents of triethylamine at ambient temperature. The mixture is stirred for 10 to 90 minutes at 20 to 80xc2x0 C. After cooling, water is added and the mixture is stirred. The product that crystallises out is filtered off, washed with water and dried. After recrystallisation from ethyl acetate it is filtered and dried.
Stage Vxe2x86x92III
In a preferred embodiment of the process according to the invention for preparing the compound of formula III:
the compound of formula V is reacted with a C1-6 carboxylic acid or a reactive derivative thereof in the presence of a base, preferably a C1-6 carboxylic acid chloride in the presence of a tertiary amine, particularly acetyl chloride, in the presence of N-ethyldiisopropylamine.
The acylation is expediently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, ethyl acetate, dioxane, benzene, toluene, acetonitrile or sulpholane optionally in the presence of an inorganic or organic base, preferably a tertiary amine at temperatures of xe2x88x9220 to 150xc2x0 C., preferably at temperatures from xe2x88x9210 to 120xc2x0 C., particularly at ambient temperature. However, it may also be carried out with the free acid, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionylchloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxybenzotriazole, N,Nxe2x80x2-carbonyldiimidazole or N,Nxe2x80x2-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C. The reaction is generally carried out at normal pressure, using 0.8 to 2.0, preferably 0.9 to 1.5, particularly 1.0 to 1.5 equivalents of a carboxylic acid derivative, based on 1 equivalent of the compound of formula V. The reaction is generally complete under the conditions specified after 15 to 300 minutes, preferably 30 to 120 minutes. The crude product obtained is generally purified by recrystallisation or may be further processed in the next step without any other purification.
In a particularly preferred embodiment 1.1 to 1.5, particularly about 1.3 equivalents of acetylchloride are added dropwise to a mixture of 1 equivalent of formula V, N-ethyldiisopropylamine and ethyl acetate at 0 to 20xc2x0 C. The mixture is stirred for 60 to 120 minutes at ambient temperature and washed with water at 40 to 90xc2x0 C. The product is recrystallised from ethanol, filtered off and dried.
Stage VIxe2x86x92V
In a preferred embodiment of the process according to the invention for preparing the compound of formula V:
the compound of formula VI is reduced with a boranate, particularly with sodium boranate in the presence of a base and a polar solvent.
The reduction may be carried out by catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium/charcoal or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50xc2x0 C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
Preferably, the reduction is carried out with a boranate selected from among lithium boranate, sodium boranate and potassium boranate, expediently in a diluent such as water, methanol, ethanol, isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulphoxide, ethyleneglycolmonomethylether, ethyleneglycoldiethylether or sulpholane or mixtures of these diluents, optionally in the presence of an inorganic base, e.g. sodium carbonate, sodium hydroxide or potassium hydroxide, or a tertiary organic base, e.g. triethylamine, N-ethyldiisopropylamine or pyridine, at temperatures of xe2x88x9220 to +60xc2x0 C., preferably xe2x88x9210 to +20xc2x0 C. The reaction is generally carried out at normal pressure using 0.9 to 4.0, preferably 1.1 to 1.9, more particularly 1.6 to 1.8 mol of a boranate, based on 1 mol of the compound of formula VI. The reaction is generally complete under the conditions specified after 15 to 600 minutes, preferably 60 to 240 minutes. The crude product obtained is generally purified by recrystallisation or may be further processed in the next step without any other purification.
In a particularly preferred embodiment a mixture of about 1.75 mol sodium borohydride, water and sodium hydroxide in the form of an approximately 2N sodium hydroxide solution is added dropwise to a mixture of 1 mol of a compound of formula VI and ethyl acetate at 0 to 5xc2x0 C. The mixture is stirred for another 1 to 3 hours at 0 to 20xc2x0 C. and then heated to 60 to 80xc2x0 C. The suspension is filtered and cooled to about 0xc2x0 C. The product that crystallises out is isolated and dried.
Tetrachlorohomopurine Stagexe2x86x92VI
The reaction with the amine of formula VII is expediently carried out in a diluent such as methanol, ethanol, isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulphoxide, ethyleneglycolmonomethylether, ethyleneglycoldiethylether, sulpholane or water or mixtures of these diluents, particularly THF, optionally in the presence of an inorganic base, e.g. sodium carbonate or potassium hydroxide, or a tertiary organic base, e.g. triethylamine, N-ethyldiisopropylamine or pyridine, at temperatures of 0 to 80xc2x0 C., preferably 5 to 50xc2x0 C., particularly 10 to 30xc2x0 C. The reaction is generally carried out at normal pressure, using 0.7 to 1.2, preferably 0.8 to 1.0, particularly about 0.95 equivalents of a compound of formula VII based on 1 equivalent of water-dampened tetrachlorohomopurine. The reaction is generally complete under the conditions specified after 15 to 600 minutes, preferably 30 to 180 minutes. The crude product obtained is generally purified by recrystallisation or may be further processed in the next step without any other purification.
In a particularly preferred embodiment, a solution of 0.8 to 0.95 equivalents of the amine of formula VII, particularly 3-chloro-4-fluoraniline in THF, is added dropwise to a mixture of 1 equivalent of tetrachlorohomopurine and tetrahydrofuran at 10 to 20xc2x0 C. The mixture is stirred for 10 to 50 minutes at ambient temperature, activated charcoal is added and stirring is continued for another 10 to 20 minutes at ambient temperature. Then the reaction mixture is filtered in water and the filter residue is washed with THF. The aqueous suspension is stirred at ambient temperature and the product is then isolated and dried.
A major advantage of the process according to the invention is that it enables the compounds of formula I to be produced on an industrial scale starting from an easily obtainable starting material, namely 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (tetrachlorohomopurine).
Other advantageous aspects of the method according to the invention are the high space/time yields of the present process and the high yield and purity of the associated intermediate products, which can be further processed without being purified by chromatography.
The Examples that follow serve to illustrate the processes carried out by way of example for preparing the compound of formula I. They are to be understood as being possible methods given solely as examples without restricting the invention to their content.